Impact of vaccination on COVID-19 severity during the second wave in Brunei Darussalam, 2021

Objective Coronavirus disease (COVID-19) vaccinations have been shown to prevent infection with efficacies ranging from 50% to 95%. This study assesses the impact of vaccination on the clinical severity of COVID-19 during the second wave in Brunei Darussalam in 2021, which was due to the Delta variant. Methods Patients included in this study were randomly selected from those who were admitted with COVID-19 to the National Isolation Centre between 7 August and 6 October 2021. Cases were categorized as asymptomatic, mild (symptomatic without pneumonia), moderate (pneumonia), severe (needing supplemental oxygen therapy) or critical (needing mechanical ventilation) but for statistical analysis purposes were dichotomized into asymptomatic/mild or moderate/severe/critical cases. Univariate and multivariable analyses were conducted to identify risk factors associated with moderate/severe/critical disease. Propensity score-matched analysis was also performed to evaluate the impact of vaccination on disease severity. Results The study cohort of 788 cases (mean age: 42.1 ± 14.6 years; 400 males) comprised 471 (59.8%) asymptomatic/mild and 317 (40.2%) moderate/severe/critical cases. Multivariable logistic regression analysis showed older age group (≥ 45 years), diabetes mellitus, overweight/obesity and vaccination status to be associated with increased severity of disease. In propensity score-matched analysis, the relative risk of developing moderate/severe/critical COVID-19 for fully vaccinated (two doses) and partially vaccinated (one dose) cases was 0.33 (95% confidence interval [CI]: 0.16–0.69) and 0.62 (95% CI: 0.46–0.82), respectively, compared with a control group of non-vaccinated cases. The corresponding relative risk reduction (RRR) values were 66.5% and 38.4%, respectively. Vaccination was also protective against moderate/severe/critical disease in a subgroup of overweight/obese patients (RRR: 37.2%, P = 0.007). Discussion Among those who contracted COVID-19, older age, having diabetes, being overweight/obese and being unvaccinated were significant risk factors for moderate/severe/critical disease. Vaccination, even partial, was protective against moderate/severe/critical disease.


Setting
The management of the COVID-19 outbreak in Brunei Darussalam has been previously described. 11In brief, at the start of the second wave, all patients with COVID-19 were admitted to the NIC.However, over the course of the second wave, increasing numbers of mild cases of COVID-19 were admitted to the newly established community isolation centres for isolation and treatment.Symptomatic patients with moderate or severe disease, as well as those with mild disease plus significant comorbidities (i.e.diabetes, obesity, older age and end-stage renal failure) and persistent fever, dyspnoea or diarrhoea continued to be admitted to the NIC for management and treatment.

Study population
Patients included in the study were those admitted to the NIC between 7 August and 6 October 2021, who tested positive for COVID-19 through laboratory-confirmed reverse transcription-polymerase chain reaction (RT-PCR) testing.To counter the effect of changing NIC admission criteria and ensure equal representation across the spectrum of COVID-19 disease severity in the study population, patients were randomly selected (using Microsoft Excel's random number generator) at three time points (early August, mid-September and early October).Patients aged ≤18 years, pregnant women and patients with end-stage renal disease were excluded, as these patient subgroups were not eligible for vaccination at the time of the start of the second wave.

Data collection
Patient data were prospectively collected using a specially designed database that was set up to monitor and aid the management of patients admitted to the NIC.Information on patients' demographic characteristics (age, sex) was collected, as well as data on relevant clinical risk factors such as body mass index (BMI), diabetes mellitus, hypertension and dyslipidaemia.Patients' vaccination status was retrieved from patients' Bru-HIMS health records and coded as either "complete" (if patients had received their second dose at least 14 activity against the Beta variant (B.1.351). 10However, vaccination remained important for reducing the risk of infection and severe disease and mitigating the impact of COVID-19.
In Brunei Darussalam, the first wave of COVID-19 started on 9 March 2020 and was rapidly controlled, with the last community spread documented on 6 May 2020.Control measures included public health and social measures such as mask wearing and restrictions on movements and social gatherings, coupled with testing, close monitoring and surveillance of cases, and regular review and updating of infection control and outbreak management protocols in response to the evolving nature of the pandemic. 11An important part of the national response, and one that was instrumental in the containment of the first wave, was the establishment of a designated centre, the National Isolation Centre (NIC), to isolate and treat all positive cases. 11

Study design
This study used a retrospective cohort study design to assess the impact of vaccination on the risk of developing severe COVID-19 among patients who were admitted to the NIC during the second wave of the COVID-19 outbreak in Brunei Darussalam between 7 August and 6 October 2021.days prior to contracting COVID-19), "partial" (if patients had received their first dose at least 14 days prior to contracting COVID-19 or less than 14 days had elapsed since their second dose) or "unvaccinated" (if patients were unvaccinated prior to contracting COVID-19 or less than 14 days had elapsed since their first dose). 4

Clinical severity categories
Patients were assigned to one of five categories according to clinical severity: asymptomatic, mild (symptomatic without pneumonia), moderate (clinical or radiological evidence of pneumonia), severe (moderate respiratory decompensation requiring non-invasive supplementary oxygen) and critical (respiratory decompensation requiring intubation and mechanical ventilation or extracorporeal membrane oxygenation support). 11Patients' clinical severity was recorded daily for management decisionmaking.

Primary outcome
The primary outcome was defined as the highest clinical severity category attained by the patient during their hospitalization.For the purposes of subsequent statistical analyses, the outcome variable was dichotomized into two categories: asymptomatic/mild disease and moderate/severe/critical disease.Patients who died were included in the moderate/severe/critical category, irrespective of cause of death.Deaths were recorded as a COVID-19 death if supported by evidence of COVID-19 pneumonia.

Statistical analysis
All statistical analyses were performed using IBM SPSS software (version 26).Patient characteristics, stratified by disease severity, were summarized in a descriptive analysis.Continuous data were presented as a mean ± standard deviation and compared using the independent Student's t-test.Categorical data were presented as frequency and percentages and compared using Pearson's chi-squared test.Univariate analyses, with disease severity as the outcome, were used to explore which potential risk factors (demographic characteristics, clinical risk factors and vaccination status) were associated with more severe disease.Significant risk factors (P < 0.05) derived from univariate analysis were then input into a multivariable logistic regression model to calculate the odds ratio (OR) for each significant variable.
To investigate the effectiveness of vaccination in reducing the clinical severity of COVID-19 cases, patients were matched 1:1 according to their vaccination status (vaccinated or unvaccinated) using propensity scores derived from summing the probabilities of being vaccinated given patients' demographic characteristics (age and sex) and the presence of selected clinical risk factors (diabetes, hypertension, hyperlipidaemia and overweight/obesity).These probabilities were derived using binary logistic regression.The relative risk (RR) of more severe COVID-19 disease comparing the two propensity score-matched groups (vaccinated and unvaccinated) was estimated using a 2x2 contingency table chi-squared test.This comparison was repeated in a subgroup analysis designed to determine the effect of complete and partial vaccination status on disease severity.Additional analyses were conducted in selected COVID-19 patient subgroups: patients aged ≥45 years, overweight/obese patients and patients with diabetes mellitus.Estimates of the relative risk reduction (RRR), the absolute risk reduction (ARR) and the number needed to treat (NNT) were also derived from the analyses of the matched groups.P < 0.05 was considered statistically significant.

Study population
Between 7 August and 6 October 2021, there were 7702 recorded cases of COVID-19 in Brunei Darussalam, of which 1666 were admitted to the NIC.Nine hundred patients were randomly selected (300 from each of three time periods), 112 of whom were subsequently excluded based on the above-mentioned exclusion criteria.The study population thus comprised a total of 788 patients (Fig. 1).
Around one third (n = 237, 30.1%) of patients had received at least one dose of a COVID-19 vaccine (75 completed two doses, 162 completed one dose); 551 (69.9%) were unvaccinated.Within the critical severity category (n = 21), there were 18 unvaccinated patients (85.7%) and three (14.3%)partially vaccinated patients.None of the critical patients had been fully vaccinated.There were 28 deaths in the study sample; in this group of patients, 22 (78.6%) were unvaccinated, 6 (21.4%) were partially vaccinated and none were fully vaccinated.

Univariate and multivariable logistic regression analyses
Univariate analysis showed that age, diabetes mellitus, hypertension, dyslipidaemia, overweight/obesity and vaccination status were significantly associated with COVID-19 disease severity (Table 1).
After adjustment in a multivariable logistic regression analysis, age, diabetes mellitus, overweight/ obesity and vaccination status remained significantly associated with COVID-19 disease severity.The odds of developing moderate/severe/critical disease were significantly lower in those who had been vaccinated, even partially (OR: 0.45, 95% confidence interval [CI]: 0.30-0.67,P < 0.001) (Table 2).

Propensity score-matched analyses
A total of 357 patients were matched on their propensity score for vaccination: 177 vaccinated (65 complete and 112 partial) and 180 unvaccinated.There were no significant differences in the demographic and clinical characteristics between the vaccinated and   a Vaccinated patients included those who had received at least one dose of a COVID-19 vaccine at least 14 days prior to their COVID-19 infection.Unvaccinated patients included those who had not received a COVID-19 vaccine or had received their first dose within 14 of their COVID-19 infection.b Pearson's chi-squared test used with P < 0.05 considered significant.CI: confidence interval; RR: relative risk; RRR: relative risk reduction.
a For subgroup analysis by vaccination status, propensity score matching resulted in the exclusion of three patients, one in the partially vaccinated and two in the unvaccinated group.Hence, the total number of patients included in this analysis was 354.
b Fully vaccinated patients included those who had received two doses of COVID-19 vaccine, with the second dose administered at least 14 days before COVID-19 infection.Partially vaccinated patients were those who had received one dose of a COVID-19 at least 14 days before their COVID-19 infection; patients who had received their second dose within 14 days of their COVID-19 infection were also included in this category.Unvaccinated patients included those who had not received a COVID-19 vaccine or had received their first dose within 14 days of their COVID-19 infection.c Pearson's chi-squared test used with P < 0.05 considered significant.Other studies have also found that patients with these three clinical risk factors -older age, diabetes mellitus and overweight/obesity -are at increased risk for severe COVID-19 disease and death and are thus considered to be high-risk groups. 12-17The higher risk associated with older age groups can be attributed to a waning immunity Separate subgroup analyses were conducted for older patients (aged ≥45 years), those with diabetes mellitus and those being overweight/obese.Vaccination was significantly protective against developing more severe disease in the overweight/obese group with a RR of 0.63 (95% CI: 0.44-0.89)and a RRR of 37.2% (95% CI: 10.8-55.7%).In contrast, among the older population (aged ≥45 years) and those with diabetes mellitus, there was no difference in the risk of more severe disease between those who had received at least one dose of a COVID-19 vaccine and those who were unvaccinated (Table 6).

DISCUSSION
Among a cohort of 788 patients who tested positive for COVID-19 and were admitted to the NIC during the factors or the type of vaccine (mRNA or inactivated), was protective against developing moderate/severe/critical COVID-19.Fully vaccinated patients, i.e. those who had received two doses of vaccine, were 67% less likely to be in the moderate/severe/critical group compared with those who were unvaccinated.Conversely, an unvaccinated patient had three times the risk of moderate/ severe/critical disease than a fully vaccinated patient.Even being partially vaccinated, i.e. having received one dose of vaccine at least 14 days prior to infection, was associated with a RR of 0.62 and RRR of 38% (relative to unvaccinated patients).
While directly comparable studies are limited in number, our results are broadly consistent with those from other studies.For example, in a case-control study involving 119 partially vaccinated patients who were age-and sex-matched to 476 unvaccinated patients, vaccination was associated with a 69.3% RRR in death (and an ARR of 22.3%). 26Likewise, a recent communitywide serosurvey conducted in 5310 subjects in Hong Kong Special Administrative Region, China, demonstrated that three or four doses of BNT162b2 or CoronaVac were effective against Omicron infection 7 days after vaccination (vaccine effectiveness ranged from 30% to 69%). 27owever, 100 days after vaccination, this effectiveness had waned to 6-26%. In a longitudinal study looking at antibody response to SARS-CoV-2 infection, 100% of patients aged 10-17 years retained their antibody titre 3 months after seropositive conversion; in those aged ≥40 years, this fell to 84%. 202][23] Pulmonary function tests in obese patients, in particular those with abdominal obesity, have revealed a tendency towards restrictive respiratory patterns and reduced lung volumes compared with people with a lower BMI. 24This reduction in pulmonary reserves may explain why a higher proportion of obese patients with COVID-19 decompensated rapidly and required oxygen supplementation and intubation. 14Cardiovascular risk factors such as hypertension and dyslipidaemia, previously reported to be significant risk factors for severe COVID-19 infection, 25 were not significantly more common in the moderate/severe/critical COVID-19 group in this study.This is consistent with the findings of a study from Guangzhou, China, 15 and may be specific to this variant of the virus.
Our propensity score-matched analysis showed that vaccination, independently of several clinical risk Severity of COVID-19 and impact of vaccination in Brunei Darussalam Chong et al patients, breakthrough infection despite vaccination is due to immunosenescence and a reduced effectiveness of immune response to vaccination. 19A recent study showed that one third of patients aged ≥80 years had no detectable neutralizing antibodies despite receiving two doses of a COVID-19 vaccine, whereas among those aged <60 years, only 2.2% had no detectable neutralizing antibodies. 30Data from the United States Centers for Disease Control and Prevention have confirmed that adults aged ≥50 years were 2-8 times more likely to be hospitalized with breakthrough COVID-19 infection despite being fully vaccinated. 31It has been suggested that the same immune dysregulation and dysfunction combined with chronic inflammation may account for the increased risk seen in patients with diabetes mellitus, especially if their diabetes is suboptimally controlled. 32ere are several limitations that need to be considered when interpreting our study results.First, the study group comprised a hospital-based cohort and hence the results can only be applied to other hospital settings.Second, this study did not consider the effect of treatments (e.g.steroids and remdesivir) on the outcome.However, since our primary outcome was the highest severity category obtained during hospitalization, any impact of such treatments is unlikely to have affected the allocation of the primary outcome.Third, the clinical severity categories used in our study were based on a severity scale used in South-East Asia to triage patients for admission to hospital and may differ from severity categories used elsewhere.However, our definition for the moderate/severe/critical group was equivalent to the definition of severe COVID-19 used in published randomized controlled trials evaluating the efficacy of COVID-19 vaccine candidates. 4Importantly, the categories used were simple and effective for daily monitoring of patients and reporting to the Ministry of Health.Fourth, this study did not evaluate the effectiveness of the different types of COVID-19 vaccines but rather combined all vaccines (mRNA or inactivated) into a single group.In addition, this study only assessed the impact of vaccination on the Delta strain, and therefore the results will not be applicable to subsequent newer strains, such as Omicron.Lastly, we used propensity score matching to generate similar comparison groups for our analysis, thus eliminating the effect of known important confounding variables on our effect estimates for the impact of vaccination on disease severity.We of the 54 fully vaccinated patients admitted to hospital developed moderate/severe/critical disease, almost twice as many as our cohort of patients with complete vaccination status. 28Nevertheless, both this study and ours identified older age (≥80 years), overweight (BMI >25 kg/m 2 ), cardiovascular disease and diabetes as risk factors for more severe COVID-19 disease.
Our real-world findings further support and strengthen the evidence from clinical trials for the efficacy of vaccination in preventing severe COVID-19.In a study using the Comirnaty vaccine, the protective effect of the vaccine in preventing symptomatic COVID-19 infection was evident as early as 12 days after the first dose with an efficacy of 52%, which increased to 95% at 7 days after the second dose. 3Similarly, a trial of Spikevax reported an efficacy of 95.2% in preventing symptomatic COVID-19 infection 14 days after the first dose. 4sed on our analysis, we estimated that the NNT to prevent one case of moderate/severe/critical disease in this cohort was six.That is to say, for every six people vaccinated with at least one dose of a COVID-19 vaccine who subsequently contracted COVID-19, one was prevented from developing moderate/severe/critical disease.This suggests that the impact of vaccination was large for the Delta variant outbreak in Brunei Darussalam.Our findings also provide strong evidence in favour of vaccination, especially in settings with limited specialist health-care resources, such as bed capacity in intensive care units, and thus limited capacity to care for severely ill COVID-19 patients.More broadly, and as repeatedly demonstrated by the COVID-19 pandemic, vaccination will undoubtedly continue to play an important role in managing disease outbreaks, even those caused by less virulent strains such as Omicron. 29reliminary analysis of more recent data collected during subsequent outbreaks of COVID-19 in Brunei Darussalam dominated by the Omicron variant, which are not reported here, suggests that the effectiveness of vaccination in protecting against moderate to critical disease remains significant despite the reduced virulence of the Omicron variant.
For elderly consider that propensity score matching is a suitable alternative in pandemic settings where conducting a randomized control study may not be feasible, ethical or cost-effective.
In conclusion, in a cohort of patients hospitalized with COVID-19 during the second wave in Brunei Darussalam, which was dominated by the Delta variant (B.1.617.2),vaccination was effective in reducing the risk for moderate/severe/critical disease by up to 67%.For every six fully or partially vaccinated cases infected with the Delta variant, one moderate/severe/critical case can be prevented, thereby reducing health-care utilization.The protective effect of vaccination was also observed in the group of overweight or obese patients, although to a lesser degree (37%).As the pandemic progresses or transitions to an endemic phase, the severity of COVID-19 infections will continue to impact high-risk populations, and thus the case for vaccination remains.
Brunei Darussalam started rolling out vaccination with four WHO-prequalified vaccines (Vaxzevria [AstraZeneca], BBIBP-CorV [Sinopharm], Comirnaty [Pfizer-BioNTech] and Spikevax [Moderna]) on 3 April 2021, 4 months before the start of the second wave on 7 August 2021.The second wave was due to the Delta variant of SARS-CoV-2, 11 a more contagious variant than the original and Alpha strains.This study assesses the effectiveness of vaccination in preventing severe disease among patients with COVID-19 in Brunei Darussalam during the second wave and investigates the role of vaccination in modifying selected known risk factors for severe to critical COVID-19.

Table 1 . Demographic characteristics and clinical risk factors of 788 COVID-19 cases, by disease category, admitted to the National Isolation Centre between 7 August and 6 October 2021, Brunei Darussalam
All recorded laboratory-confirmed RT-PCR positive COVID-19 cases in Brunei Darussalam, 7 August to 6 October 2021 (N = 7702): 1666 patients admitted to the National Isolation Centre (NIC), of whom 1388 recovered and were discharged 300 patients randomly selected from each of three time periods (n = 900): 7-23 August, 24 August-13 September, 14 September-6 October 788 patients included for univariate and multivariable logistic regression analysis Propensity score calculated based on vaccination status 357 patients were propensity score-matched and selected for analysis of the effect of vaccination on reducing COVID-19 disease severity (177 vaccinated patients compared with 180 unvaccinated patients) BMI: body mass index; COVID-19: coronavirus disease; RT-PCR: reverse transcription-polymerase chain reaction.SD: standard deviation.a Bold P values are statistically significant (<0.05).b Analysis of variance (ANOVA) comparison of mean age.c Pearson's chi-squared test.

Table 3 . Demographic characteristics and clinical risk factors of 357 COVID-19 cases that were propensity score matched by vaccination status
: absolute risk reduction; CI: confidence interval; NNT: number needed to treat; RR: relative risk; RRR: relative risk reduction. ARR

Table 6 . Subgroup analysis to explore the effect of older age, overweight/obesity and diabetes on the association between vaccination status and the risk of developing more severe COVID-19 disease in a cohort of 357 propensity score-matched cases admitted to the National Isolation Centre between 7 August and 6 October 2021, Brunei Darussalam
: absolute risk reduction; CI: confidence interval; NNT: number needed to treat; RR: relative risk; RRR: relative risk reduction.a Vaccinated patients included those who had received at least one dose of a COVID-19 vaccine at least 14 days prior to their COVID-19 infection.Unvaccinated patients included those who had not received a COVID-19 vaccine or had received their first dose within 14 of their COVID-19 infection.b Pearson's chi-squared test used with P < 0.05 considered significant. ARR